Better Lucky Than Good

“The most exciting phrase to hear in science, the one that heralds new discoveries, is not ‘Eureka!’, but ‘That’s funny’,” author and chemistry professor, Isaac Asimov, once observed.

Many important scientific concepts owe their discovery to pure chance…or even dumb luck. The award for the most famous accidental finding goes to Sir Alexander Fleming.

Fleming, as part of his on-going research, would grow bacteria cultures in Petri dishes. But in the summer of 1928, Fleming got a little careless. He left a few of his Petri dishes exposed to the air, and then went on vacation. When he returned from vacation, he happened to notice that one of the Petri dishes containing the Staphylococcus aureus bacteria had been contaminated by a mold — a mold that killed the bacteria!…

We should all feel very grateful for Sir Fleming’s fantastically poor lab practice; it brought us penicillin. Similarly, the serendipitous discovery of one of today’s most striking scientific breakthroughs, RNA interference (RNAi), was almost poetic. It all started with a purple petunia…

Back in 1986, the molecular geneticist, Rich Jorgenson, was trying to produce a very dazzling flower using genetic-engineering methods. He settled on the goal of making a particularly purple petunia, since petunias were one of the few flowers that were easy to genetically reengineer.

He inserted a second copy of the petunia gene that controls the production of purple pigment, hoping that increasing the amount of such code within the cells would lead to greater production of purple pigment. Instead, the flower turned white. He called this paradoxical effect “cosuppression,” but no one understood at the time why adding more of a gene turned that gene off.

It took more than a decade of research across several organisms to figure out why the flower did the opposite of what was expected. It turns out that Jorgenson had stumbled upon a mechanism to switch off gene expression, a process now known as RNAi.

Here’s the story in a nutshell: The genes that make up the DNA of any organism are like little “information packets.” Genes “tell” proteins how to assemble and therefore what precise function they are to perform in a cell. But to deliver this information, the genes need an intermediary — a messenger. This messenger is called “messenger RNA,” or “mRNA.” Thus, RNAi blocks or “interferes” with mRNA, thereby blocking the genetic instructions the mRNA is trying to deliver to the proteins. The protein is not fabricated; the gene remains “silent.”

In 1998, American biologists, Andrew Fire and Craig Mello, formally described the mechanism behind RNAi. They clarified many confusing and contradictory experimental observations and revealed a natural mechanism to control the flow of genetic information.

Fire and Mello took the scientific community by storm when they pieced together the molecular machinery behind the RNAi process. RNAi basically mimics a natural cell defense against virus infection that no one knew existed until 1998. They were awarded the Nobel Prize in Physiology or Medicine 2006 for their discovery of RNAi. Rightly so… Armed with data from genome-sequencing projects, researchers can now develop RNAi-based gene-silencing therapies on a breathtaking scale.

Already, scientists can easily tailor in vitro pieces of RNA that match up to a  specific strand of mRNA. Such synthetic molecules are called “small interfering RNA,” or siRNA. Theoretically, any gene can be switched off by siRNA.

Now think about it… If siRNA can essentially turn off genes by destroying them through a sort of sequence-detection, then what stops them from curing diseases? By knocking down the activity of one or several genes, RNAi could potentially block a plethora of diseases.

The most promising target for RNAi-based therapies seems to be cancer. Since overactive genes often cause cancer, quelling their activity could halt certain cancers in their tracks. But viral infections are also important potential targets for RNAi-based therapies.  Reducing the activity of key viral genes could cripple a virus. Numerous studies have already hinted at the promise of RNAi for treating viral infections. In laboratory-grown human cells, investigators have stopped the growth of HIV, polio, hepatitis C and other viruses.

One decade after Fire and Mello’s groundbreaking research, RNAi-based therapies finally entered clinical trials. The reason it took so long for siRNA therapies to enter clinical trials is that scientists struggled to devise a safe and effective way to deliver siRNA. But researchers have recently made tremendous progress toward improving the efficiency, specificity and, as a consequence, the safety of the siRNA delivery systems.

Thanks to these advances, several biotech companies have moved RNAi-based therapies into Phase I trials. Silence Therapeutics (Symbol: SLN on the London Stock Exchange), for example, is in Phase I trials with “Atu027,” a therapy to combat solid tumors (melanoma, sarcoma, ovarian cancer, pancreatic cancer etc).

Silence has a very promising RNAi-delivery mechanism, as does Calando Pharmaceuticals, a subsidiary of Arrowhead Research (Symbol: ARWR). Calando is in Phase I trials with CALAA-01, a cancer-targeting formulation that uses the company’s proprietary RNAi-delivery system, “RONDEL.” Silence and Calando are just two examples of the biotech companies that are leading the charge into RNAi-based therapies.

It took serendipity, a groundbreaking discovery, and 25 years of hard work. But RNAi-based therapies are finally moving from concept to reality. We’ll keep watching this space very closely.


Severine Kirchner,
for The Daily Reckoning